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PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport

Activation of protein kinase C (PKC) has previously been shown to ameliorate the cholesterol transport defect in Niemann Pick Type C1 (NPC1) cells, presumably by increasing the soluble levels of one of its substrates, vimentin. This activity would then restore the vimentin cycle in these cells and a...

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Autores principales: Tamari, Farshad, Chen, Fannie W., Li, Chunlei, Chaudhari, Jagrutiben, Ioannou, Yiannis A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744505/
https://www.ncbi.nlm.nih.gov/pubmed/23977398
http://dx.doi.org/10.1371/journal.pone.0074169
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author Tamari, Farshad
Chen, Fannie W.
Li, Chunlei
Chaudhari, Jagrutiben
Ioannou, Yiannis A.
author_facet Tamari, Farshad
Chen, Fannie W.
Li, Chunlei
Chaudhari, Jagrutiben
Ioannou, Yiannis A.
author_sort Tamari, Farshad
collection PubMed
description Activation of protein kinase C (PKC) has previously been shown to ameliorate the cholesterol transport defect in Niemann Pick Type C1 (NPC1) cells, presumably by increasing the soluble levels of one of its substrates, vimentin. This activity would then restore the vimentin cycle in these cells and allow vimentin-dependent retrograde transport to proceed. Here, we further investigate the effects of PKC activation in NPC1 cells by evaluating different isoforms for their ability to solubilize vimentin and correct the NPC1 cholesterol storage phenotype. We also examine the effects of PKC activators, including free fatty acids and the PKC-specific activator diazoxide, on the NPC1 disease phenotype. Our results indicate that PKC isoforms α, βII, and ε have the greatest effects on vimentin solubilization. Furthermore, expression or activation of PKCε in NPC1 cells dramatically reduces the amount of stored cholesterol and restores cholesterol transport out of endocytic vesicles. These results provide further support for the contribution of PKCs in NPC1 disease pathogenesis and suggest that PKCs may be targeted in future efforts to develop therapeutics for NPC1 disease.
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spelling pubmed-37445052013-08-23 PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport Tamari, Farshad Chen, Fannie W. Li, Chunlei Chaudhari, Jagrutiben Ioannou, Yiannis A. PLoS One Research Article Activation of protein kinase C (PKC) has previously been shown to ameliorate the cholesterol transport defect in Niemann Pick Type C1 (NPC1) cells, presumably by increasing the soluble levels of one of its substrates, vimentin. This activity would then restore the vimentin cycle in these cells and allow vimentin-dependent retrograde transport to proceed. Here, we further investigate the effects of PKC activation in NPC1 cells by evaluating different isoforms for their ability to solubilize vimentin and correct the NPC1 cholesterol storage phenotype. We also examine the effects of PKC activators, including free fatty acids and the PKC-specific activator diazoxide, on the NPC1 disease phenotype. Our results indicate that PKC isoforms α, βII, and ε have the greatest effects on vimentin solubilization. Furthermore, expression or activation of PKCε in NPC1 cells dramatically reduces the amount of stored cholesterol and restores cholesterol transport out of endocytic vesicles. These results provide further support for the contribution of PKCs in NPC1 disease pathogenesis and suggest that PKCs may be targeted in future efforts to develop therapeutics for NPC1 disease. Public Library of Science 2013-08-15 /pmc/articles/PMC3744505/ /pubmed/23977398 http://dx.doi.org/10.1371/journal.pone.0074169 Text en © 2013 Tamari et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tamari, Farshad
Chen, Fannie W.
Li, Chunlei
Chaudhari, Jagrutiben
Ioannou, Yiannis A.
PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport
title PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport
title_full PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport
title_fullStr PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport
title_full_unstemmed PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport
title_short PKC Activation in Niemann Pick C1 Cells Restores Subcellular Cholesterol Transport
title_sort pkc activation in niemann pick c1 cells restores subcellular cholesterol transport
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744505/
https://www.ncbi.nlm.nih.gov/pubmed/23977398
http://dx.doi.org/10.1371/journal.pone.0074169
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